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Title: High-throughput functional analysis for the identification of targets for cancer therapy.
Author: Mendes-Pereira, Ana Maria
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research (University Of London)
Date of Award: 2013
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The term cancer comprises a family of genetic diseases that share a fundamental biological commonality, the abnormal proliferation of cells. Targeted cancer therapies are strategies intended to exploit particular cancer features, for the delivery of tailored treatments that spare injury to normal tissues. Comparative functional profiling through RNA interference (RNAi) screens, offers a powerful framework for the identification of both, novel appropriate targets for therapy and, in the case of existent targeting agents, markers of susceptibility to drug resistance. In this thesis, RNAi technology, which renders gene suppression and provides an indirect model for the pharmaceutical inhibition of a target protein, was used to systematically survey the effect of targeting unbiased collections of individual genes, on the modulation of: (i) survival of cells deficient in PTEN a gene frequently mutated in cancer, and (ii) breast cancer response to the breast cancer drug tamoxifen. The high prevalence of PTEN tumour suppressor deregulation in cancer gives it considerable therapeutic pertinence. Until fairly recently, tumour suppressor loss-offunction was considered an undruggable cancer specific aberration, but with the unravelling of synthetically sick/lethal associations, targeting cancers that harbour absent or dysfunctional tumour suppressors is now possible. In the first part of this thesis, two complementary approaches were used with the purpose of identifying targets that sensitise PTEN deficient tumour cells. Both strategies shared the use of isogenic cell models to recapitulate endogenous PTEN loss-of-function, Firstly, a hypothesis-driven approach, demonstrated that DNA repair defects exhibited in the context of PTEN deficiency sensitise to treatment with PARP inhibitors. Secondly, a screening approach focussed on a siRNA kinome set, revealed vulnerability of PTEN deficient cells to the targeting of mitotic regulators such as TTK and PLK4, and led to the identification of a novel potential PTEN synthetic partner, NLK, targeting of which could potentially be useful in tackling a range of tumourigenic conditions characterised by PTEN deficiency. 4 In the second half of this thesis, attention was directed at investigating a pioneering targeted therapy, tamoxifen, which inhibits estrogen receptor (ER) signalling. Despite being the most common and effective treatment for breast cancer types reliant on estrogen stimulation, the effectiveness of this endocrine treatment is, nevertheless, limited by the frequent development of resistance, and the mechanisms attributed to this are not yet fully deciphered. A genome-wide RNAi screen was conducted to uncover novel determinants of tamoxifen sensitivity, and a compendium of molecules validated as possible modulators of response to tamoxifen. Inspection of retrospective clinical data showed that for some of these genes, their expression levels in patients with ER+ disease treated with tamoxifen correlated with relapse outcome, suggesting that monitoring of these genes could aid prediction of patient response to antiestrogens. Similar analyses indicated the suitability of targeting certain candidate genes to prevent or combat cancer recurrence in hormonal therapy. Several previously unexplored determinants of tamoxifen response were identified.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available